N-derivatives of 4-amino-4-desoxy-rifamycin sv and preparation

ABSTRACT

N-derivatives of 4-amino-4-desoxy-rifamycin SV are prepared by reacting in an organic solvent medium rifamycin O with a secondary amine having lower alkyl, lower alkenyl, cycloalkyl, phenyl, cycloalkyl-lower alkyl or phenyl-lower alkyl substituent groups, or wherein a hetero N compound is substituted for the secondary amine, to give the titular compounds which are recovered from the reaction medium in usual ways. The products have antimicrobial activity.

United States Patent l 191 Crlcchio a N-DERIVATIVES OF 4-AMlNO-4-DESOXY-RIF AMY CIN SV AND PREPARATION Renato Cricchio, Varese, Italy Assignee: Gruppo Lepetit S.p.A., Milano, Italy Filed: Jan. 14, 1972 Appl. No.: 217,955

Inventor:

[30] Foreign Application Priority Data Jan. 18, 1971 Italy 19460/71 US. Cl. 260/239.3 P, 424/244, 424/267,

424/274, 424/250, 424/248 Int. Cl. C07d 99/02, C07d 99/04 Field of Search 260/2393 P [56] References Cited OTHER PUBLICATIONS Cricchi et CUFIIL v t-ttlatu asg i 3,821,199 1 June 28, 1974 Primary Examiner-Henry R. Jiles Assistant Examiner-Robert T. Bond Attorney, Agent, or FirmTheodore Post; C. Kenneth Bjork 5 7] ABSTRACT or wherein a hetero N compound is substituted for the secondary amine, to give the titular compounds which are recovered from the reaction medium in usual ways. The products have antimicrobial activity.

10 Claims, N0 Drawings N-DERIVATIVES OF 4-AMlN0-4-DESOXY-RIFAMYCIN sv AND PREPARATION SUMMARY OF THE INVENTION This invention relates to new antimicrobial compounds. More particularly the invention relates to new rifamycin SV derivatives of the formula MeMe - wherein Me represents methyl, R and R independently represent lower alkyl, lower alkenyl, cycloalkyl, phenyl, cycloaIkyI-lower aIkyl,-phenyI-lower alkyl, or taken together form with the nitrogen atom a heterocyclic ring with one or more hetero-atoms, optionally substituted by lower alkyl or lower carbalkoxy groups.

In the inventive compounds, the lower alkyl groups represent straight or branched aliphatic chains containing from I to 8 carbon atoms, the lower alkenyl groups contain from 3 to 8 carbon atoms, the aliphatic moiety of the phenyl-lower alkyl groups contain from 1 to 5 carbon atoms, and the cycloalkyl groups contain from 5 to 8 carbon atoms. The hcterocyclic moieties are generaily represented by fully hydrogentated 5- to 8- membered ring.

In accordance with the present invention, it has been found that rifamycin O can be allowed to react with an amine deriv t ve fths orm la wherein R and R have the same significance as above,

seed n he fidlwinaetsw ,7

Me Me i MeCO OH 0 a late MeCOO Me M NH Me f 0 A i The reaction is performed by reacting one molecular proportion of rifamycin O with about two molecular proportions of the selected amine in an organic solvent at a temperature from about 15 to about 35 C. After a period of time, varying between about 12 and about hours according to the reaction rate, thin layer chromatography on silica gel, using as eluent a mixture CHCl :MeOH 9: I, shows the disappearance of rifamycin O and the formation of a new product having an Rf lower than that of rifamycin 0, together with a moderate quantity of rifamycin B and trace amounts of byproducts. The recovery of the end products is effected by evaporating the organic layer and crystallizing the crude products by a suitable organic solvent such as, for example, ethyl acetate or precipitating the same end products from ethyl acetate by addition of another inert organic solvent.

In accordance with these methods a number of N- derivatives of 4-amino-4-desoxy-rifamycin SV can be prepared, representatives of which are listed hereinbelow. This list is not to be considered limitative of the scope of the present invention.

4-dimethylamino-4-desoxy-rifamycin SV 4-( N-methyl-N-benzyl )amino-4-desoxy-rifamycin SV 4-piperidino-4-desoxy-rifamycin SV 4-( 4-methylpiperidino )-4-desoxy-rifamycin SV 4-dialkylamino-4-desoxy-rifamycin SV 4-hexamethylenimino-4-desoxy-rifamycin SV 4-dibutylamino-4-desoxy-rifamycin SV 4-dihexylamino-4-desoxy-rifamycin SV 4-dioctylamino-4-desoxy-rifamycin SV 4-dibenzylamino-4-desoxy-rifamycin SV 4-bis(phenethyl )amino-4-desoxy-rifamycin SV 4-pyrrolidino-4-desoxy-rifamycin SV 4-dicycIohexyIamino-4-desoxy-rifamycin SV 4-(N-methyl-N-cyclohexyl)-amino4-desoxyrifamycin SV 4-( 4-phenethyl- I -pipe razinyl )-4-desoxy-rifamycin SV 4-( 2,6-dimethyl-4-benzyl- I -piperazinyl )-4-desoxyrifamycin SV 4-heptamethyleneimino-4-desoxy-rifamycin SV 4- N-ethyl-N-( 3-phenylpropyl ]amino-4-desoxyrifamycin SV 4-bis(2-pentenyl)amino-4-desoxy-rifamycin SV 4-(N-propyl-N-cyclopentyl)amino-4-desoxyrifamycin SV 4-bis(2,4,4-trimethyl-2-pentenyl)amino-4-desoxyrifamycin SV 4-[N-methyl-N-(2,4-dimethoxypenethyl)]amino-4- desoxy-rifamycin SV V 4-(N-ethyl-N-phenyl)amino-4-desoxy-rifamycin SV 4-[N-buty1-N-(p-chlorophenyl)]amino-4-desoxyrifamycin SV 4- N-( 3cyclohexylpropyl )-N-ethyl ]amino-4-desoxyrifamycin SV 4-morpholino-4-desoxy-rifamycin SV 4-(1 piperazinyl)-4-desoxy-rifamycin SV 4-( 4-carbethoxyl -piperazinyl )-4-desoxy-rifamycin SV 4-(4-methy1-1-piperazinyl)-4-desoxy-rifamycin SV 4-( N-hexyl-N-phenethyl )amino-4-desoxy-rifamycin SV 4-( 3-propylmorpholino-4-desoxy-rifamycin SV The novel rifamycins of this invention are yellow substances, moderately soluble both in acid medium, such as for example 0.1 N HCl, and in basic medium,'such as for instance saturated solutions of NaI-ICO The compounds, on the contrary, are very soluble in several organic solvents like acetone, ethyl acetate, methanol, benzene and chlorinated hydrocarbons. Their structure has been established through physical data, that is proton magnetic resonance (pmr), mass, infrared, ultraviolet and visible spectra. The pmr spectrum of these compounds shows the disappearance of the signals of the -CH group of the spirolactonic ring of the rifamycin at 4.7 8 units and the appearance of the new signals due to the 4-amino group.

The mass spectrum of the N,N-dimethyl derivative shows the molecular ion at m/e 724, in accordance with the calculated molecular weight. The infrared spectrum shows the disappearance of the absorption band at 1822 cm, which is characteristic of the spirolac- DETAILED DESCRIPTION OF THE INVENTION The following representative examples describe the manner and process of making and using the invention to enable art-skilled persons to make and use the same and set forth the best mode of carrying out the invention.

Example 1: 4-Dimethylamino-4-desoxy-rifamycin SV To a solution of 3 g. of rifamycin O in 100 ml. of tet- 10 rahydrofuran, 3.5 ml. of an ethanolic solution of dithe residue is dissolved in 100 ml. of ethyl acetate and washed twice with ml. of phosphate buffer, pH 7.38. The organic layer is dried and concentrated under reduced pressure to a small volume. The product crystallizes out, and, after chilling is collected, washed with 20 ethyl acetate and dried, yielding 600 mg. of 4- dimethylamino-4-desoxy-rifamycin SV, melting at 16778 C. Spectrophotometric data registered in phosphate buffer, pH 7.38 A max (mp) 302, e 18,800; A max (mu) 418, 6 22,000.

Example 2: 4-(N-Methyl-N-benzyl)-amino-4-desoxyrifamycin SV To a solution of 4 g. of rifamycin O in 150 ml. of tetrahydrofuran, 1.250 g. of N-methyl-benzylamine are added at room tempreature. After 40 hours the reaction is completed and the solution is concentrated to dryness. The residue is dissolved in 10 ml. of chloroform and placed on a column of 200 g. of silica gel, prewashed with chloroform, then eluted with a mixture of chloroform-methanol. The first eluate is discarded, the

tonic ring of the rifamycin O. further eluate is collected, concentrated to dryness, dis- The polarographic analysis does not show the reducsolved in 20 m1. of ethyl acetate and poured under agition wave (E =+0.03 volt) of the system 1,4-quinone 1tation into a breaker containing 150 ml. of hexane. The

4 :hydroquinone characteristic of rifamycin of type SV. precipitated product is collected and dried, yielding 1 i The compounds of this invention show a high degree g. of the title compound, melting at 13955 C. with of antimicrobial activity. Particularly remarkable is jdecomposition. Spectrophotometric data registered in their activity against Staphylococcus aureus, Streptococphosphate buffer, pH 7.38 )1 max (mu) 305, 6 16,600

cus hemolyticus, Diplucoccus pneumoniae and Mycobac- )1 max (mp) 420, 6 18,400.

' Ierium tuberculosis. In representative tests, all of the Examples 3-15 compounds inhibit in vitro the growth of one or more The products listed in Table I have been prepared of the above microorganisms at concentrations ranging using a procedure exactly similar to that used for makfrom 0.00 5 to yhnl. ing the N methyl-N-benzyl derivative of Example i TABLE I R! Spectrophotometric data (d) -N Melting Example Yield, point, Xrnax. Amax. number R percent C. (m 0 (my) 0 a 021I6 20 1704s 305 14,840 424 10, 050

6 /CH2CH=OH2 8.4 -50 303 10,000 410 20,000

TABLE :291 52995 RI Spectrophotometric data (d) -N Melting Example 1 Yield, point, Xmax. Xmas. number R percent C. (m e (my) e 7 CHz-C H 25 155-80 300 17, 700 416 19, 800

CHPQ

N CH:

12 N/ v 20 170-76 303 17, 200 I 420 19,400

N NH

N NC 0 C2H N N-CH:

Deeomposed.

4 Registered in phosphate buffer, pH 7.38.

What is claimed is: :.A rif myPMY e e? of h fe mi' wherein Me represents methyl, R and R independently represent 1 to 8 carbon atom alkyl, 3 to 8 carbon atom .alkenyl, 5 to 8 carbon atom cycloalkyl, phenyl, phenyl- Met) 6. The compound of claim 1 which is 4(4-methyl- 5 piperidino)-4-desoxy-rifamycin SV.

7. The compound of claim ,1 which is 4-morpholino- 4-desoxy-rifamycin SV.

8. The compound of claim 1 which is 4-(lpiperazinyl)-4-desoxy-rifamycin SV.

9. The compound of claim 1 which is 4-(4- carbethoxyl -piperazinyl )-4-desoxy-rifamycin SV.

10. A process for making a rifamycin SV derivative QEEQQZ JEPJQ Me Me wherein Me represents methyl, R and R independently represent 1 to 8 carbon atom alkyl, 3 to 8 carbon atom alkenyl, 5 to 8 carbon atom cycloalkyl, phenyl, 5 to 8 carbon atom cycloalkyll to 8 carbon atom alkyl, phenyll to 5 carbon atom alkyl, or together with the nitrogen atom form a heterocyclic ring of the group consisting of piperidino, pyrrolidino, piperazino and morpholino, optionally substituted by a lower alkyl or a lower carbalkoxy group, which comprises contacting r a ye n 0 with a i aefctb fqmvl wherein R and R have the same significance as above from the reaction medium. 

2. The compound of claim 1 which is 4-dimethylamino-4-desoxy-rifamycin SV.
 3. The compound of claim 1 which is 4-diethylamino-4-desoxy-rifamycin SV.
 4. The compound of claim 1 which is 4-piperidino-4-desoxy-rifamycin SV.
 5. The compound of claim 1 which is 4-(2-methyl-piperidino)-4-desoxy-rifamycin SV.
 6. The compound of claim 1 which is 4-(4-methyl-piperidino)-4-desoxy-rifamycin SV.
 7. The compound of claim 1 which is 4-morpholino-4-desoxy-rifamycin SV.
 8. The compound of claim 1 which is 4-(1-piperazinyl)-4-desoxy-rifamycin SV.
 9. The compound of claim 1 which is 4-(4-carbethoxy-1-piperazinyl)-4-desoxy-rifamycin SV.
 10. A process for making a rifamycin SV derivative of the formula 